The present invention relates to aryl-8-azabicyclo[3.2.1]octane and aryl-8-azabicyclo[3.2.1]oct-2-ene derivatives having pharmacological activity, and to their use in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.
Pharmaceuticals which enhance serotonergic neurotransmission are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affection drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier (5-HT-T).
The present invention relates to a new class of molecules which have the ability to act at the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
Some of the present molecules have a second activity as partial agonists/inhibitors of the serotonin 1A receptor (5-HT1A). Since SSRIs require several weeks before a full therapeutic effect is seen, their mechanism of action can""t solely be explained by the inhibition of 5-HT-T. It is believed that this delayed effect is due to the involvement of 5-HT1A autoreceptors. It has been previously suggested (Artigas et al. TiPs, 1993, 14, 262) that the efficacy of reuptake inhibitors may be attenuated by the activation of 5-HT1A receptors which results in the reduced firing rate of 5-HT neurons. Repeated SSRI administration, causing desensitization of 5-HT1A receptors, is postulated to be required before the antidepressant effect of these compounds is seen. Support for desensitization of 5-HT1A in humans is shown by an obsessive-compulsive disorder (OCD) study (Lesch et al. Psychopharm. 1991, 105, 415), where patients given repeated treatment with SSRIs developed tolerance to the hypothermic response induced by the administration of the 5-HT1A antagonist ipsapirone. Thus a dual SSRI/5-HT1A antagonists should provide antidepressant activity with a rapid onset of action. Studies using a combination of an SSRI (fluoxetine) and a 5-HT1A antagonists (pindolol) appear to support this hypothesis (Artigas et. al. Arch. Gen. Psychiat. 1994, 51, 248 and Perez et al. Arch. Gen. Psychiat 1999, 56, 375).
Aryloxyalkyl amines have previously been shown to effect 5-HT-reuptake. U.S. Pat. No. 5,614,523 (Audia et al.) discloses a series of indoloxyethylpiperazines which affect the 5-HT1A and 5-HT-T receptors. U.S. Pat. No. 5,627,196 (Audia et al.) discloses a series of indoloxyethyltetrahydropyridines and indolyoxyethylpiperidinols which affect the 5-HT1A and 5-HT-T receptors. U.S. Pat. No. 5,741,789 (Hibschman et al.) teaches a series of quinolinoxyethylpiperidines which affect the 5-HT1A and 5-HT-T receptors. U.S. Pat. No. 5,789,402 (Audia et al.) discloses a series of indoloxyethylpiperidines which affect the 5-HT1A and 5-HT-T receptors. The current invention differs from the these patents in that the 8-azabicyclo[3.2.1]octane and 8-azabicyclo[3.2.1]oct-2-ene ring structures are used instead of the corresponding piperidines/tetrahydropyridines.
8-Azabicyclo[3.2.1]octanes and 8-azabicyclo[3.2.1]oct-2-enes have previously been shown to effect 5-HT-T reuptake. WO 9713770 (Moldt et al.) teaches a series of phenyl tropenes which affect the 5-HT-T receptor. WO 9716451 (Scheel-Krxc3xcgger et al.) discloses a series of fused tropane derivatives which act as neurotransmitter reuptake inhibitors. WO 9965492 (Audia et al.) provides a series of aryl tropenes/tropanes that affect the 5-HT-T receptor in. The current invention differs from these references in that an aryloxy alkyl chain has been attached to the aryl 8-azabicyclo[3.2.1]octane and aryl 8-azabicyclo[3.2.1]oct-2-ene structures.
The present invention comprises compounds represented by the formula I: 
wherein:
A is an optional residue which combines with the carbon atoms to which it is attached to complete a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dioxinyl, pyrrolyl, imidazolyl, pyridinyl, pyridazynyl or pyrimidinyl group;
X is NH, O or S;
n is an integer from 0 to 3;
Ar1 is phenyl or pyridyl substituted with 0-2 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, and trifluoromethoxy groups and combinations thereof;
Ar2 is indolyl, benzimidazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzyl, benzofuryl, or benzothienyl, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups;
and all crystalline forms and pharmaceutically acceptable salts thereof.
The present invention further comprises a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
The present invention also comprises methods of making and using the compounds and formulations of this invention, which methods are described in further detail below.
A preferred aspect of this invention comprises compounds of formula I wherein:
A is a residue which combines with the carbon atoms to which it is attached to complete a cyclopentyl, cyclohexyl, pyrrolyl, or pyridinyl, group
X is an NH, O or S moiety
n is 1-2;
Ar1 is a phenyl group substituted with 0-2 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, cyano, trifluoromethyl, hydroxyl, and trifluoromethoxy groups and combinations thereof;
Ar2 is indolyl, phenyl, naphthyl, benzofuryl, or benzothienyl, substituted with 0-2 C1-C3 alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups;
and all crystalline forms and pharmaceutically acceptable salts thereof.
More preferred compounds of this invention are compounds of formula I wherein:
A is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl, or pyridinyl, group
X is an NH, or O moiety
n is 1;
Ar1 is phenyl substituted with 0-2 groups selected from C1-C3 alkoxy, halo, trifluoromethyl, trifluoromethoxy, and combinations thereof;
Ar2 is indolyl, naphthyl, benzofuryl, or benzothienyl, substituted with 0-2 halo, cyano, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups;
and all crystalline forms and pharmaceutically acceptable salts thereof.
In this specification, the term alkyl, whether used alone or as part of another group, includes straight and branched chain alkyl groups containing from 1 to 3 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, are encompassed by the term alkyl. The alkyl group may be substituted or unsubstituted. The aforementioned number of carbon atoms in the alkyl group refers to carbon backbone and does not include carbon atoms of substituents, such as alkoxy substitutions and the like.
Alkoxy, whether used alone or as part of another group include straight and branched chain alkoxy groups containing from 1 to 3 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, are encompassed by the term alkoxy. The alkoxy group may be substituted or unsubstituted. The aforementioned number of carbon atoms in the alkoxy group does not include carbon atoms of substituents, such as alkyl substitutions and the like.
Halogen or halo as used herein means chlorine, bromine, iodine and fluorine.
Highly preferred compounds of the present invention include:
4-[2-(3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-ethoxy]-1H-indole or a pharmaceutically acceptable salt thereof;
3-{8-[2-(1H-Indol-4-yloxy)ethyl]-8-azabicyclo[3.2.1]oct-2-en-3-yl}-1H-indole or a pharmaceutically acceptable salt thereof;
2-[3-(1H-indol-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethyl 5-quinolinyl ether or a pharmaceutically acceptable salt thereof;
8-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene or a pharmaceutically acceptable salt thereof;
6-methoxy-N-{2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethyl}-8-quinolinamine or a pharmaceutically acceptable salt thereof;
6-Chloro-N-{2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethyl}-8-quinolinamine or a pharmaceutically acceptable salt thereof;
N-{2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethyl}-8-quinolinamine or a pharmaceutically acceptable salt thereof;
6-Methoxy-8-[2-(3-naphthalen-2-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)-ethoxy]-quinoline or a pharmaceutically acceptable salt thereof;
8-[2-(Indan-4-yloxy)-ethyl]-3-naphthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene or a pharmaceutically acceptable salt thereof;
4-{2-[3-(6-Methoxy-naphthalen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-ethoxy}-1H-indole or a pharmaceutically acceptable salt thereof;
3-Naphthalen-2-yl-8-[2-(3-trifluoromethyl-phenoxy)-ethyl]-8-aza-bicyclo[3.2.1]oct-2-ene or a pharmaceutically acceptable salt thereof;
4-[2-(3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-1H-indole or a pharmaceutically acceptable salt thereof;
4-{2-[3-(3,4-Dichloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-ethoxy}-1H-indole or a pharmaceutically acceptable salt thereof;
3-{8-[3-(1H-indol-4-yloxy)propyl]-8-azabicyclo[3.2.1]oct-2-en-3-yl}-1H-indole or a pharmaceutically acceptable salt thereof;
4-[3-(3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-propoxy]-1H-indole or a pharmaceutically acceptable salt thereof;
4-{3-[3-(3,4-Dichlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]propoxy-1H-indole or a pharmaceutically acceptable salt thereof;
8-{2-[3-(2-Naphthyl)-8-azabicyclo[3.2.1]oct-8-yl]ethoxy}quinoline or a pharmaceutically acceptable salt thereof; and,
8-({2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}sulfanyl) quinoline or a pharmaceutically acceptable salt thereof.
It is understood that the definition of the compounds of formula I, when Ar contains asymmetric carbons, encompasses all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques known in the art.
Pharmaceutically acceptable salts are those derived from organic and inorganic acids such as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, oxalic, fumaric, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and the like. Where Ar contain a carboxyl group, salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg), and the like.
The compounds of formula I have been found to have affinity for the 5-HT reuptake transporter. They are therefore useful in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.
The present invention further provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. The compositions are preferably adapted for oral or subcutaneous administration. However, they may be adapted for other modes of administration.
The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Any of the solid carriers known to those skilled in the art may be used with the compounds of this invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention. The compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. Suitable examples of liquid carriers for oral and parenteral administration include water, alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be either liquid or solid composition form.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions typically may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in a conventional manner, for example, in a manner similar to those used for known antihypertensive agents, diuretics and xcex2-blocking agents.
The compounds of formula I may be synthesized as described below:
In one aspect of the present invention, compounds of formula I where X=NH, O or S and A=pyrrole may be prepared by reacting the corresponding Ar2-8-azabicyclo[3.2.1]-octane or -octene compound with the corresponding pyrrolyl-Ar1xe2x80x94Xxe2x80x94(CH2)nxe2x80x94CH2-halide in the presence of an appropriate solvent and base, as exemplified in Scheme I. Thus a compound of formula III is reacted with a compound of formula IV in the presence of an appropriate solvent such as DMSO, DMF, EtOH, or MeOH and in the presence of a base such as K2CO3, Et3N, or i-Pr2NEt at 80xc2x0 C. to give a compound of formula II. 
Naphthyl-8-azabicyclo[3.2.1]octenes/naphthyl-8-azabicyclo[3.2.1]octanes of formula III may prepared according to Scheme II. Thus bromonapthalene (formula V) and other bromoarenes may be lithiated by reaction with n-BuLi, s-BuLi or t-BuLi in an etherial solvent such THF, DME or Et2O, followed by addition of N-Boc-tropinone to give tropinol (formula VI). Treatment of tropinol with TFA or other acids in a solvent such as CH2Cl2, CHCl3 or Cl(CH2)2Cl causes deprotection of the Boc group as well as elimination of H2O to give naphthyl-8-azabicyclo[3.2.1]octene (formula VII). In addition to Boc, other nitrogen protecting groups useful for these reactions are well known by the skilled artisan (for example, see Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley Interscience, New York, 1999) and may be used in the practice of this invention. Reduction of naphthyl-8-azabicyclo[3.2.1]octene (formula VII) to the corresponding saturated naphthyl-8-azabicyclo[3.2.1]octane (formula Vila) can be accomplished via hydrogenation conditions using a precious metal catalyst such as palladium on carbon in an appropriate solvent such as EtOH, EtOAc or MeOH. 
Compounds of formula IV may be prepared according to Scheme III. Thus, thio, amino and oxyindoles are reacted with 2-chloromethanol, 2-chloroethanol, 2-chloro-n-propanol or 2-chloro-n-butanol in the presence of diethyl- or diisopropylazodicarboxylate, and triphenylphosphine, in a suitable solvent such as THF, CH2Cl2 or MeCN to produce IV according to the procedure of Mitsunobu in Synthesis 1981, 1; recent review: Hughs, Org. React. 1992, 42, 337. Similar thio, amino and oxy-heterocyclic compounds may be prepared similarly. 
Compounds of formula I where X=NH, O or S, Ar1 is phenyl and A=pyridinyl (NH, O and S substituents are in the 8-position of the quinoline) require a different preparation route due to the position of the quinoline nitrogen. Compounds of formula I, where X=NH, Ar1 is phenyl and A=pyridinyl may be prepared by reacting the corresponding 8-haloquinoline with the corresponding Ar2-8-azabicyclo[3.2.1]oct(a/e)ne-CH2xe2x80x94(CH2)nxe2x80x94NH2 compound in the presence of NaOt-Bu and a suitable catalyst, as exemplified in Scheme IV. Thus, compounds of formula IX are reacted with compounds of formula X, catalytic Pd2dba3 or Pd(OAc)2, catalytic BI NAP or other suitable phosphine ligands known to a skilled artisan, in the presence of NaOt-Bu, in PhMe or THF at 80xc2x0 C. to give compounds of type VII in accordance with the procedure descirbed by Buchwald in Angew. Chem., Int. Ed. Engl. 1995, 34, 1348.
Compounds of formula IX may be prepared according to Scheme V. Alkylation of the secondary amine in a compound of formula VII or formula VIIa with 2-(N-Boc amino)ethyl chloride (prepared according to the procedure of Tanaka (Chem. Pharm. Bull. 1988, 36, 3125) in the presence of Et3N in a solvent such as CH2Cl2 or DMF gives the N-Boc ethylamine derivative of formula XI. Removal of the Boc group is accomplished by treatment with TFA in a solvent such as CH2Cl2 to give naphthyl-8-azabicyclo[3.2.1]octene/naphthyl-8-azabicyclo[3.2.1]octane of formula IX. 
In the case where the bromoarene is a 3-bromoindole, 3-indolyltropene (formula IX) may be synthesized according to Scheme VI. Thus 3-Br-N-TBS-indole (formula XII), prepared according to the procedure of Bosch in J. Org. Chem. 1994, 59, 10, is lithiated using an alkyl lithium such as t-BuLi and then reacted with N-Boc-tropinone to give tropinol (formula XIII). Deprotection of both the TBS groups and elimination of H2O occurs with TFA or other acids to give 3-indole-8-azabicyclo[3.2.1]octene XIV. Reduction using hydrogen gas, a precious metal catalyst such as palladium on carbon in a suitable solvent such as EtOH, MeOH, or EtOAc gives indole-8-azabicyclo[3.2.1]octane XIVa. 
8-Bromoquinolines, such as a compound according to formula X, may be synthesized as shown in Scheme VII. 2-Nitroanilines of formula XV may be converted to their corresponding nitroquinolines (formula XVI) via a Skraup reaction using glycerol, 3-NO2PhSO3Na in hot concentrated H2SO4 according to Palmer in J. Chem. Soc. 1962, 3645, reduction of the nitroquinoline to the corresponding quinolineamine (formula XVII) may be accomplished using H2, a precious metal catalyst such as Pd on carbon in a solvent such as EtOAc or EtOH or iron, NH4Cl and H2O in an alcoholic solvent. Diazotization of the compound of formula XVII using NaNO2 in HBr, followed by heating in the presence of CuBr and additional HBr at an elevated temperature produces the 8-bromoquinoline of formula X. 
Compounds of formula I where X=O, and A-Ar1 form an 8-quinolinyl may be prepared by reacting the corresponding 8-hydroxyquinoline with the corresponding Ar2-8-azabicyclo[3.2.1]oct(a/e)ne-CH2xe2x80x94(CH2)n-halide compound in the presence of NaH, as exemplified in the following Scheme VIII. Thus a compound of formula XIX is reacted with compound of formula XX, a NaH dispersion in mineral oil, in an appropriate solvent such as DMSO or DMF at 80xc2x0 C. to produce the compound of formula XVIII. 
Naphthyl-8-azabicyclo[3.2.1]octene/naphthyl-8-azabicyclo[3.2.1]octane (formula XIX) may be prepared according to Scheme IX. Thus naphthyl-8-azabicyclo[3.2.1]octenes/naphthyl-8-azabicyclo[3.2.1]octanes of formulae VII and VIIa are reacted with 2-bromoethanol in the presence of K2CO3 at 80xc2x0 C. in an appropriate solvent such as DMF, DMSO or EtOH to produce the compound of formula XXII. Conversion to the corresponding chloride (formula XIX) may be accomplished using MsCl, a tertiary amine base such as Et3N or i-Pr2NEt in a solvent such as CH2Cl2, Cl(CH2)2Cl or DMF. 
The sequence in Scheme VI may also be applied to indoles of formulae XIV and XIVa to synthesize the corresponding indoles of formula XIX or formula XVII.
Compounds of formula I where X=S may be prepared by reacting the corresponding 8-thioquinoline with the corresponding Ar2-8-azabicyclo[3.2.1]oct(a/e)ne-CH2xe2x80x94(CH2)n-halide compound in the presence of NaH, as exemplified in the following Scheme X. Thus a compound of formula XIX may be reacted with a compound of formula XXIII in a suitable solvent such as DMSO, DMF, MeCN or EtOH at an elevated temperature such as 50xc2x0 C. to produce a compound of formula XXII. The synthesis of compounds of formula XIX is illustrated in Scheme IX, above. 
The synthesis of compounds of formula XXIII is shown in Scheme XI, in which a compound of formula X is reacted with an alkyllithium such as n-BuLi, s-BuLi or t-BuLi in an etherial solvent such THF or Et2O, allowed to stir for 0 to 60 minutes and then quenched with a slurry of S8 in benzene or toluene according to the procedure of Bergman et al. Isr. J. Chem. 1969, 7, 477.
The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula I are of particular use in the treatment of diseases affected by disorders of the serotonin.
The present invention further provides a method of treating depression and anxiety in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.
The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.